- Human CD1 comprises a family of antigen presentation molecules with a unique tissue distribution that includes skin. Experiments performed in the principal investigator's laboratory indicate that CD1-restricted T cells recognize lipid antigens and can contribute to cell-mediated immunity in leprosy. In this application, the principal investigator proposes to explore the immunobiology of antigen presentation by CD1 in human disease, by investigating the cutaneous lesions of leprosy. The Specific Aims are as follows: 1) The structure of antigens presented by human CD1 molecules will be elucidated by deriving CD1-restricted T cells from both tuberculoid and lepromatous leprosy lesions. The principal investigator proposes to determine whether distinct lipid antigens and/or CD1 restricting elements differentially contribute to the host response to infection. 2) The critical antigen-binding sites for lipid and lipoglycan antigens on the molecular surface of the ligand-binding groove of CD1b will be mapped by engineering mutant CD1 molecules that can be used in antigen-presentation and antigen-binding studies. 3) The functional role of CD1-restricted T cells in skin will be investigated by comparing CD1-restricted T cells from tuberculoid vs. lepromatous lesions according to the pattern of secreted cytokines, cytolytic and antimicrobial activity, and their ability to provide help for B cells in the production of antibodies. The studies proposed are intended to provide a comprehensive and in-depth view of CD1-restricted T cell function in relation to a model of human skin disease, with particular emphasis on their role in immunity. Such insights would provide new avenues for development of new treatments for a variety of human skin and infectious diseases.